Title

Author

Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Jeffrey D. Winkler

Abstract

When detected early and surgically removed, melanoma has a cure rate greater than 90%. However, when the cancer is either unresectable or goes undetected until late-stage metastases develop, the five-year survival rate drops to 20%. Unfortunately, the current standard of care suffers from chemotherapeutic resistance, where the outcome results in a high rate of patient mortality. Recent clinical studies have demonstrated hydroxychloroquine-mediated inhibition of autophagy presents a promising strategy as an adjuvant therapy for melanoma treatment. Regrettably, in clinical trials hydroxychloroquine has not demonstrated reliable potency, at the maximum tolerated doses, in producing autophagy inhibition.

Work by the Winkler and Amaravadi Laboratories has focused on developing a series of dimeric chloroquine-based autophagy inhibitors. Our findings encouraged us to develop a library of dimeric inhibitors, based on hydroxychloroquine and its congener, quinacrine. These not only inhibit autophagy, but also possess single agent anti-cancer activity previously unobserved with small-molecule autophagy inhibitors. Through our efforts we have designed DQ661, a dimeric quinacrine autophagy inhibitor which simultaneously inhibits key drivers of oncogenesis: autophagy, mTOR kinase signaling, and macropinocytosis. We have also discovered an analogous dimeric chloroquine inhibitor, DC661, which is a potent inhibitor of autophagy and cancer cell proliferation. Utilizing these compounds, we have identified a molecular binding partner for our dimeric inhibitors: protein palmitoyl thioesterase 1 (PPT1), a key regulator of palmitoylation within the lysosome. We are currently developing chemical tools to study the role of PPT1 in cancer biology.